This invention relates to catheters used to deliver radiation to prevent or slow restenosis of an artery traumatized such as by percutaneous transluminal angioplasty (PTA).
PTA treatment of the coronary arteries, percutaneous transluminal coronary angioplasty (PTCA), also known as balloon angioplasty, is the predominant treatment for coronary vessel stenosis. Approximately 300,000 procedures were performed in the United States in 1990 and nearly one million procedures worldwide in 1997. The U.S. market constitutes roughly half of the total market for this procedure. The increasing popularity of the PTCA procedure is attributable to its relatively high success rate, and its minimal invasiveness compared with coronary by-pass surgery. Patients treated by PTCA, however, suffer from a high incidence of restenosis, with about 35% or more of all patients requiring repeat PTCA procedures or by-pass surgery, with attendant high cost and added patient risk.
Recent attempts to prevent restenosis by use of drugs, mechanical devices, and other experimental procedures have had limited long term success. Stents, for example, dramatically reduce acute reclosure, and slow the clinical effects of smooth muscle cell proliferation by enlarging the minimum luminal diameter, but otherwise do nothing to prevent the proliferative response to the angioplasty induced injury.
Restenosis is now believed to occur at least in part as a result of injury to the arterial wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by hyperplastic growth of vascular cells in the region traumatized by the angioplasty which is termed neointimal hyperplasia. Neointimal hyperplasia narrows the lumen that was opened by the angioplasty, regardless of the presence of a stent, thereby necessitating a repeat PTCA or other procedure to alleviate the restenosis.
Preliminary studies indicate that intravascular radiotherapy (IVRT) has promise in the prevention or long-term control of restenosis following angioplasty. IVRT may also be used to prevent or delay stenosis following cardiovascular graft procedures or other trauma to the vessel wall. Proper control of the radiation dosage, however, appears to be important to inhibit or arrest hyperplasia without causing excessive damage to healthy tissue. Overdosing of a section of blood vessel can cause arterial necrosis, inflammation, hemorrhaging, and other risks discussed below. Underdosing will result in inadequate inhibition of smooth muscle cell hyperplasia, or even exacerbation of hyperplasia and resulting restenosis.
The prior art contains many examples of catheter based radiation delivery systems. The simplest systems disclose seed train type sources inside closed end tubes. An example of this type of system can be found in U.S. Pat. No. 5,199,939 to Dake. In order to separate the radiation source from the catheter and allow re-use of the source, a delivery system is disclosed by U.S. Pat. No. 5,683,345 to Waksman et al. where radioactive source seeds are hydraulically driven into the lumen of a closed end catheter where they remain for the duration of the treatment, after which they are pumped back into the container. Later disclosures integrated the source wire into catheters more like the type common in interventional cardiology. In this type of device, a closed end lumen, through which is deployed a radioactive source wire, is added to a conventional catheter construction. A balloon is incorporated to help center the source wire in the lumen. It is supposed that the radioactive source wire would be delivered through the catheter with a commercial type afterloader system produced by a manufacturer such as Nucletron, BV. These types of systems are disclosed in Liprie U.S. Pat. No. 5,618,266, Weinberger U.S. Pat. No. 5,503,613, and Bradshaw U.S. Pat. No. 5,662,580.
In the systems disclosed by Dake and Waksman, the source resides in or very near the center of the catheter during treatment. However, it does not necessarily reside in the center of the artery. The systems disclosed by Weinberger and Bradshaw further include a centering mechanism, such as an inflatable balloon, to overcome this shortcoming. In either case, the source activity and energy must be high enough to overcome absorption loss encountered as the particles traverse the lumen of the blood vessel to get to the target tissue site in the vessel wall. Higher activity and energy sources, however, can have undesirable consequences. First, the likelihood of radiation inadvertently affecting untargeted tissue is higher because the absorption factor per unit tissue length is lower. Second, the higher activity and energy sources are more hazardous to the medical staff and thus require additional shielding during storage and additional precaution during use. In addition, the source of any activity or energy may or may not be exactly in the center of the lumen, so the dose calculations are subject to error factors due to non-uniformity in the radial distance from the source surface to the target tissue. The impact of these factors is a common topic of discussion at recent medical conferences addressing Intravascular Radiation Therapy, such as the Trans Catheter Therapeutics conference, the Scripps Symposium on Radiotherapy, the Advances in Cardiovascular Radiation Therapy meeting, the American College of Cardiology meeting, and the American Heart Association Meeting.
The impact on treatment strategy is discussed in detail in a paper discussing a removable seed system similar to the ones disclosed above (Tierstein et al., Catheter based Radiotherapy to Inhibit Restenosis after Coronary Stenting, NEJM 1997; 336(24):1697-1703). Tierstein reports that Scripps Clinic physicians inspect each vessel using ultrasonography to assess the maximum and minimum distances from the source center to the target tissue. To prevent a dose hazard, they will not treat vessels where more than about a 4xc3x97 differential dose factor (8-30 Gy) exists between the near vessel target and the far vessel target. Differential dose factors such as these are inevitable for a catheter in a curvilinear vessel such as an artery, and will invariably limit the use of radiation and add complexity to the procedure. Moreover, the paper describes the need to keep the source in a lead transport device called a xe2x80x9cpigxe2x80x9d, as well as the fact that the medical staff leaves the catheterization procedure room during the treatment. Thus added complexity, time and risk is added to the procedure caused by variability of the position of the source within the delivery system and by the activity and energy of the source itself.
In response to these dosimetry problems, several more inventions have been disclosed in an attempt to overcome the limitations of the high energy seed based systems. These systems share a common feature in that they attempt to bring the source closer to the target tissue. For example, U.S. Pat. No. 5,302,168 to Hess teaches the use of a radioactive source contained in a flexible carrier with remotely manipulated windows; Fearnot discloses a wire basket construction in U.S. Pat. No. 5,484,384 that can be introduced in a low profile state and then deployed once in place; Hess also purports to disclose a balloon with radioactive sources attached on the surface in U.S. Pat. No. 5,302,168; Hehrlein discloses a balloon catheter coated with an active isotope in WO 96/22121; and Bradshaw discloses a balloon catheter adapted for use with a liquid isotope in U.S. Pat. No. 5,662,580. The purpose of all of these inventions is to place the source closer to the target tissue, thus improving the treatment characteristics of dosimetry.
In a non-catheter based approach, U.S. Pat. No. 5,059,166 to Fischell discloses an IVRT method that relies on a radioactive stent that is permanently implanted in the blood vessel after completion of the lumen opening procedure. Close control of the radiation dose delivered to the patient by means of a permanently implanted stent is difficult to maintain because the dose is entirely determined by the activity of the stent at the particular time it is implanted. In addition, current stents are generally not removable without invasive procedures. The dose delivered to the blood vessel is also non-uniform because the tissue that is in contact with the individual struts of the stent receive a higher dosage than the tissue between the individual struts.
Additional problems arise when conventional methods, such as ion implantation, are used to make a radioactive source for IVRT. Hehrlein describes the use of direct ion implantation of active P-32 in his paper xe2x80x9cPure xcex2-Particle-Emitting Stents Inhibit Neointima Formation in Rabbitsxe2x80x9d cited previously. While successfully providing a single mode of radiation using this method, the ion implantation process presents other limitations. For example, ion implantation is only about 10 to 30% efficient. In other words, only about one to three of every ten ions put into the accelerator is implanted on the target, and the remainder remains in the machine. Thus, the radiation level of the machine increases steadily with consistent use. With consistent use, the machine can become so radioactive that it must be shut down until the isotope decays away. Therefore, the isotope used must be of a relatively short half-life and/or the amount of radiation utilized in the process must be very small, in order to shorten the xe2x80x9ccooling ofxe2x80x9d period. Moreover, the major portion of the isotope is lost to the process, implying increased cost to the final product.
Another approach to the same set of problems is to use a nuclide suspended in solution to inflate a balloon (Thornton ""114). This technique provides uniform nuclide distribution within the balloon to form the source, resulting in uniform dose patterns. Also, this configuration moves the position of the nuclide closer to the target tissue. No special catheter is required for this type of approach, and many nuclides are available in liquid form. Hence, several investigators have begun clinical studies on so called xe2x80x9c[radioactive]liquid filled balloons.xe2x80x9d
While a seemingly adequate solution to the problems of centering and dosimetry, the liquid filled balloon systems have an obvious drawback known to those familiar with the design, manufacture, or use of balloon angioplasty catheters: balloons potentially break. If a balloon is used to contain an active nuclide, a break poses an obvious health threat to the patient, physician and any nearby laboratory personnel. A break or leak may also shut down the procedure room.
In all of the foregoing designs, full containment of the isotope remains a significant challenge. The American National Standards Institute (ANSI) publishes a standard for sealed sources (ANSI N44.1-1973 Integrity and Test Specifications for Selected Brachytherapy Sources), and the US Nuclear Regulatory Commission (NRC) defines a sealed source as containing less than 5 nanoCuries (5xc3x9710xe2x88x929Curies) of removable activity. Hehrlein reported (Scripps Conference, January 1998) a balloon coated with P-32 that lost 0.5% of its contained activity in an animal study. Even with only 1 mCi of contained activity, the balloon proposed by Hehrlein would have lost 5000 nCi, well beyond NRC standards for a sealed source, and well outside of the ANSI definition of a sealed source.
Despite the foregoing, among many other advances in IVRT, there remains a need for an IVRT method and apparatus that delivers an easily controllable uniform dosage of radiation without the need for special devices or methods to center a radiation source in the lumen. Furthermore, a need remains for a radiation delivery device which is similar in use to conventional angioplasty balloon catheters, and which has a sealed source to prevent escape of radioactive species.
There is provided in accordance with one aspect of the present invention, a multilayer radiation delivery source. The source comprises a first bonding layer, having a first side, a second bonding layer, having a second side which faces toward the first side, and an isotope layer in between the first side and the second side. The first side and the second side are secured together through the isotope layer to produce a multilayer radiation delivery source. In one embodiment, the isotope layer comprises a metal salt or oxide and at least one isotope.
In accordance with another aspect of the invention, there is provided a radiation delivery balloon catheter. The catheter comprises an elongate flexible tubular body, having a proximal end and a distal end. An inflatable balloon is provided on the tubular body near the distal end, and is in fluid communication with an inflation lumen extending axially through the tubular body. A balloon bonding surface is carried on the outer surface of the balloon, and a radiation source is provided on the balloon bonding surface. An encapsulant surrounds the radiation source. The encapsulant has at least an encapsulant bonding surface on its radially inwardly facing surface for fusing with the balloon bonding surface at least proximally and distally of the radiation source.
In accordance with another aspect of the present invention, there is provided a method of treating a site within a vessel. The method comprises the steps of identifying a site in a vessel to be treated, and providing a radiation delivery catheter. The catheter has an expandable balloon with a thin film radiation source thereon. The thin film comprising a substrate layer having an isotope thereon, the isotope encapsulated by an outer encapsulant layer which is fused to the substrate throughout the length of the source. The balloon is positioned within the treatment site and inflated to bring the source in close proximity to the vessel wall. A dose of radiation is delivered from the delivery balloon to the treatment site. The balloon is thereafter deflated and removed from the treatment site.
In accordance with another aspect of the present invention, there is provided a method of simultaneously performing balloon dilation of a stenosis in a body lumen and delivering radian to the body lumen. The method comprises the steps of identifying a stenosis in a body lumen. A treatment catheter is provided, having an elongate flexible tubular body with an inflatable balloon near the distal end. A cylindrical thin film radiation delivery layer is provided on the balloon, and an encapsulant layer is positioned over the radiation delivery layer. A continuous seal is provided between the encapsulant, the radiation delivery layer, and the balloon along at least the length of the radiation delivery layer to provide a sealed source. The balloon is inserted into the lumen, transluminally advanced therethrough, and positioned within the stenosis. The balloon is inflated to radially expand the vessel in the area of the stenosis, and simultaneously deliver radiation from the thin film to and through the vessel wall.
In accordance with another aspect of the present invention, there is provided a method of simultaneously performing balloon dilation of a stenosis in a body lumen, delivering a stent, and delivering radiation to the body lumen. The method comprises the steps of identifying a stenosis in a vessel. A treatment catheter is provided, having an elongate flexible tubular body with an inflatable balloon near the distal end. A cylindrical thin film radiation delivery layer is provided on the balloon, and an encapsulant layer is positioned over the radiation delivery layer. A continuous seal is provided between the encapsulant, the radiation delivery layer, and the balloon along at least the length of the radiation delivery layer to provide a sealed source. The balloon is inserted into the lumen, transluminally advanced therethrough, and positioned within the stenosis. The balloon is inflated to radially expand the vessel in the area of the stenosis, and simultaneously deliver the stent. Radiation is also delivered from the thin film to the vessel wall.
In accordance with a further aspect of the present invention, there is provided a method of manufacturing a sealed source radiation delivery balloon catheter. The method comprises the steps of extruding a tube for producing a balloon, where the tube has a bonding layer on a radially outwardly facing surface thereof. An annular radiation delivery source is positioned or attached adjacent the balloon bonding layer. A tubular encapsulant is extruded, having a sealing layer on a radially inwardly directed surface thereof. The encapsulant is positioned concentrically around the radiation source and the balloon to produce a balloon-source-encapsulant stack, and the stack is exposed to elevated temperature to bond at least one of the balloon and the encapsulant to the source, thereby producing a sealed source.
In accordance with yet another aspect of the present invention, there is provided a multilayer radiation delivery source. The source comprises first, second, and third portions. The first portion comprises a first support layer having a first bonding layer thereon. The second portion comprises a second support layer having a second bonding layer thereon. The third portion comprises an isotope, and lies between the first and second bonding layers. The first and second bonding layers of the source begin to melt at a lower temperature than the first and second support layers.
Further features and advantages of the present invention will become apparent to those of skill in the art in view of the detailed description of preferred embodiments which follow, when considered together with the attached drawings and claims.